The present invention relates to novel substituted 4-oxy-substituted phenoxyalkyl carboxylic acid, ester and alcohol derivatives useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to a pharmaceutical method of treatment. More particularly, the novel compounds of the present invention lower low density lipoprotein cholesterol (LDL) and elevate high density lipoprotein cholesterol (HDL). Both of these effects afford protection from coronary heart disease.
The atheromatous plaque, which is the characteristic lesion of atherosclerosis, results from deposition of plasma lipids, mainly cholesteryl esters, in the intima of the arterial wall. Progressive enlargement of the plaque leads to arterial constriction and ultimately coronary heart disease. Two recent clinical trails have shown a causal relationship between serum levels of LDL- and HDL-cholesterol and coronary heart disease.
In 1984, the Lipid Research Clinics-Coronary Prevention Trial (LRC-CPPT) demonstrated for the first time that lowering LDL cholesterol would reduce coronary heart disease. Very recently the results of a five-year, 4,081 patient clinical trial published in the New England Journal of Medicine, 317, pp 1237-1245 (1987) demonstrated that the lipid regulating drug, gemfibrozil, reduced the rate of heart attack and sudden cardiac death by 34 percent in patients with elevated cholesterol levels. Gemfibrozil both lowers LDL and elevates HDL; but if the results from the LRC-CPPT study are utilized to estimate the expected reduction in incidence of heart attack and heart disease due to lowering of LDL, it amounts to approximately one-half of the effect actually observed. Thus, there appears to be little doubt as to the benefit of elevating HDL.
The compounds of this invention combine two mechanisms of action to achieve their improved activity in lowering LDL and elevating HDL. Not only do they show the same effects as gemfibrozil but, in addition, they inhibit the enzyme acyl-CoA:cholesterol acetyltransferase (ACAT).
Dietary cholesterol is absorbed from the intestinal lumen as free cholesterol which must be esterified with fatty acids. This reaction is catalyzed by ACAT. The resulting cholesteryl esters are packaged into the chylomicrons which are secreted into the lymph. Inhibitors of ACAT not only prevent absorption of dietary cholesterol but also prevent the reabsorption of cholesterol which has been released into the intestine through endogenous regulatory mechanisms, thus lowering LDL cholesterol levels and ultimately preventing the further development of atherosclerosis.
A series of phenoxyalkane acid derivatives of the formula: ##STR1## wherein R.sup.1 and R.sup.2 are the same or different lower alkyl groups; R.sup.3 is a hydrogen atom or a lower alkyl group;
R.sup.4 is a hydrogen atom or a hydroxyl protective group; PA1 R.sup.5 is a hydrogen atom, an alkyl group, or a lower alkoxy group; PA1 R.sup.6 is a hydrogen atom, a lower alkyl group, or a lower alkoxy group; PA1 Z is a group of the formula --COOR.sup.7 (where R.sup.7 is a hydrogen atom or a lower alkyl group) or a group of the formula --CH.sub.2 OR.sup.8 (where R.sup.8 is a hydrogen atom or an acyl group); and PA1 n is an integer of 1-10 is disclosed in JP 62-207236 as antioxidants which reduce lipid peroxide levels in rat liver microsomes and thus are postulated to be effective in the treatment of hyperlipemia in humans. PA1 n is an integer of 3, 4, 5, or 6; PA1 R.sup.4 is --CO.sub.2 R.sup.8 wherein R.sup.8 is hydrogen, alkyl of from one to six carbon atoms, or benzyl, or --CH.sub.2 OH; or a pharmaceutically acceptable base addition salt thereof. PA1 n is an integer of 3, 4, 5, or 6; PA1 R.sup.4 is --CO.sub.2 R.sup.8 wherein R.sup.8 is hydrogen, alkyl of from one to six carbon atoms, or benzyl, or --CH.sub.2 OH; or a pharmaceutically acceptable base addition salt thereof. PA1 n is an integer of 3, 4, 5, or 6; PA1 R.sup.4 is --CO.sub.2 R.sup.8 wherein R.sup.8 is hydrogen, alkyl of from one to six carbon atoms, or benzyl, or --CH.sub.2 OH; or a pharmaceutically acceptable base addition salt thereof may be prepared by reacting a compound of Formula II ##STR12## wherein R, R.sup.1, R.sup.2, and R.sup.3 and A.sup.1 are as defined above with a compound of Formula III ##STR13## wherein Hal is halogen and n and R.sup.4 are as defined above, in the presence of a base such as, for example, an alkali metal, alkaline earth metal carbonate or hydroxide for example, potassium carbonate, sodium carbonate, a metal hydride such as, for example, sodium hydride and the like and a solvent such as, for example, acetontrile, dimethylsulfoxide and the like at about room temperature to about the reflux temperature of the solvent for about 1 hour to about 24 hours to afford a compound of Formula Ia. Preferably, the reaction is carried out in the presence of potassium carbonate and acetonitrile at about room temperature for about 24 hours. PA1 R, R.sup.1, R.sup.2, and R.sup.3 are as defined above may be prepared by reacting a compound of Formula IIa ##STR16## wherein R, R.sup.1, R.sup.2, R.sup.3, and A.sup.2 are as defined above with a compound of Formula IIIa ##STR17## wherein Hal, n, and R.sup.8a are as defined above, using the methodology used to prepare a compound of Formula Ia from a compound of Formula II and Formula III to afford a compound of Formula Ib.
The present compounds have been chosen for their ability to lower LDL and elevate HDL and also to inhibit ACAT, and thus they possess two different mechanisms of action that complement each other. Thus, gemfibrozil speeds up the metabolism of LDL in the liver, and the excess cholesterol is released into the intestines via the bile. Normally a portion of this cholesterol is reabsorbed and ultimately recirculated in the form of new LDL. However, this is prevented in the presence of an ACAT inhibitor.